There is a widely held view that the pain of migraine headache originates from abnormally distended blood vessels in the cerebral vasculature. Dilatation in cerebral blood vessels, would cause local pressure resulting in the activation of local sensory pathways and pain. This can be the case also for the other aforementioned primary headache disorders and certain drug-induced headaches.
Many drugs are used to treat primary headache disorders such as migraine, including NSAIDs, ergot alkaloids, and several compounds that interact with different subtypes of 5-hydroxytryptamine (5-HT) receptors either as agonists (e.g. sumatriptan) or antagonists (e.g. ketanserin). However, of the drugs that interact with 5-HT receptors only the class of compounds described as 5-HT1D receptor agonists, of which sumatriptan is an example, will relieve an established headache. 5-HT1D receptor agonists are well known to cause vasoconstriction in the cerebral vasculature which supports the vasodilatation theory [Humphrey, P. P. A., Feniuk, W., Motevalian, M., Parsons A. A. and Whalley, E. T., ‘The vasoconstrictor action of sumatriptan on human dura mater in ‘Serotonin: Molecular Biology, Receptors and Functional Effects’ ed. Fozard, J. and Saxena, P. R., Birkhauser Verlag, Basel, 1991].
Exogenous administration of the potent vasodilator E-series, but not I-series, prostanoids to migraineurs is known to induce migraine-like symptoms [Carlson, L. A., Ekelund, L. G. and Oro, L. (1986) Acta Med. Scand. 183, 423; Peatfield, R. (1981) Headache 32, 98-100]. In menstrual migraines plasma concentrations of prostaglandin E2 (PGE2) are significantly increased during the pain phase of the migraine attack (Nattero, G, et al, 1989, Headache 29; 232-237). Similarly, increased levels of PGE2 have been found in saliva of common migraine patients during migraine attacks (Obach Tuca, J, et al, 1989, Headache, 29; 498-501).
This evidence, together with the effectiveness of NSAIDS (which act by inhibiting the biosynthesis of prostanoids) in both preventing or relieving a migraine attack [Karachalios, G. N., Fotiadou, A., Chrisikos, N., Karabetsos, A. and Kehagoiglou (1992) Headache 21, 190; Hansen, P. (1994) Pharmacol. Toxicol. 75, Suppl. 2, 81-82] supports the involvement of prostanoids in the aetiology of the disease. The precise role of prostanoids is unclear but could involve a combination of local vasodilator, inflammatory, and/or hyperalgesic actions. The prostanoid most often associated with such actions is PGE2.
Thromboxane A2 (TXA2), an active metabolite of arachidonic acid in human platelets, is a potent constrictor of vascular smooth muscle and aggregator of platelets. The compounds AH22191 and AH23848 (see below) and related compounds antagonise the actions of TXA2 and therefore inhibit platelet aggregation and bronchoconstriction. Hence these compounds have been claimed for use in the treatment of asthma and as anti-thrombotic agents in cardiovascular disorders. GB Patent 2,028,805 and U.S. Pat. No. 4,342,756 describe AH22921 and AH23848, respectively. These compounds have the following structures:

Additionally, both AH22921 and AH23848 have also been shown to be weak antagonists of PGE2-induced relaxation of piglet saphenous vein (pA2 values 5.3 and 5.4, respectively) through blockade of EP4 receptors [Coleman, R. A., Grix, S. P., Head, S. A., Louttit, J. B., Mallett, A. and Sheldrick, R. L. G. (1994) Prostaglandins 47, 151-168; Coleman, R. A., Mallett, A. and Sheldrick, R. L. G. (1995) Advances in Prostaglandin, Thromboxane and Leukotriene Research, 23, 241-246] but have no effect on other EP receptor subtypes EP1, EP2 and EP3.
A large number of PGE2 antagonists are known. These include oxazole derivatives, such as those disclosed in WO98/55468, dibenzoxazepine derivatives such as those of EP-A-0512399, EP-A-0512400, EP-A-0539977, WO93/09104, WO93/13082, WO94/25456 and WO95/12600, 1,2-diarylcyclopentenyl compounds such as those of U.S. Pat. No. 5,344,991, and carboxylic acids and acyl-sulphonamides such as those of WO99/47497, the disclosures of all of which are incorporated herein by reference.